CN102617549A - Method for preparing imatinib mesylate beta crystalline form - Google Patents
Method for preparing imatinib mesylate beta crystalline form Download PDFInfo
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- CN102617549A CN102617549A CN2012100528225A CN201210052822A CN102617549A CN 102617549 A CN102617549 A CN 102617549A CN 2012100528225 A CN2012100528225 A CN 2012100528225A CN 201210052822 A CN201210052822 A CN 201210052822A CN 102617549 A CN102617549 A CN 102617549A
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- sti571
- beta crystal
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- imatinib mesylate
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Abstract
The invention relates to a method for preparing an imatinib mesylate crystalline form, particularly relates to a method for preparing an imatinib mesylate beta crystalline form, which is characterized in that unformed imatinib mesylate or other crystalline forms of imatinib mesylate are dissolved in a mixture solvent of methanol and acetonitrile, insulated and crystallized at the temperature between -30 DEG C and 82 DEG C, the crystallization time is 2-48 hours, and the imatinib mesylate beta crystalline form is obtained. The method has the advantages that the preparation process is simple, a beta-crystalline form does not need to be introduced as a seed crystal, the imatinib mesylate beta crystalline form which is good in liquidity, stable in thermal forces, small in hydroscopic properties, and easy to store and process can be prepared, and the method is suitable for industrial production particularly.
Description
Technical field
The present invention relates to a kind of preparation method of STI571 crystal formation, be specifically related to a kind of preparation method of STI571 beta crystal.
Background technology
Preparation and application thereof, the especially application as antineoplastic agent of STI571 (being 4-(4-N-METHYL PIPERAZINE-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2--amino phenyl]-BM mesylate) beta crystal have been recorded among the CN 1134430C.
Novartis Pharma Schweiz AG selects the STI571 of beta crystal as the raw material of producing tablet; This crystal formation has good mobility; Also have in the more stable advantage of thermodynamics below 140 ℃, water absorbability is less relatively, therefore is easier to store and processing.But the STI571 of present beta crystal needs to introduce crystal seed and causes crystallization in the preparation process, and crystallization time is long, complex process, and yield is not high.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of STI571 beta crystal can not introduce under the condition of beta-crystal as crystal seed, makes the STI571 of beta crystal through easy technology.
The preparation method of a kind of STI571 beta crystal of the present invention; The STI571 of unformed STI571 or other crystal formation is dissolved in the mixed solvent of methyl alcohol and acetonitrile; Under-30～82 ℃ of conditions, be incubated crystallization; Crystallization time is 2～48h, obtains the STI571 beta crystal.
Wherein, preferably according to the standard of 5～30ml/g, the STI571 of unformed STI571 or other crystal formation is dissolved in the mixed solvent of methyl alcohol and acetonitrile.
In the mixed solvent of methyl alcohol and acetonitrile, methyl alcohol preferably accounts for 5～99% of mixed solvent TV, and more preferably 10～40%.The present invention adds acetonitrile in mixed solvent, can make crystallization more stable, and shortens the crystalline time, and the add-on of acetonitrile is many more, and the time is short more, has improved production efficiency greatly.
Described Tc is preferably 20～60 ℃.
Described crystallization time is preferably 2～6h.
The fusing point of the STI571 beta crystal that the present invention prepares is lower than 217 ℃, and this fusing point is defined as beginning fused temperature in the differential scanning calorimetric analysis.Shown in accompanying drawing 3.
The STI571 beta crystal that the present invention prepares is under following refraction angle 2 θ, and the relative spectrum line strength that the spectral line in its x-ray diffraction pattern has is 20 or higher: 9.5 ° (33), 13.7 ° (53), 17.2 ° (97); ° 17.9 (76), 19.8 ° (51), 20.3 ° (100), 20.8 ° (92); ° 21.8 (63), 22.5 ° (34), 23.5 ° (37); ° 29.5 (38), 30.6 ° (25), the numeral in the bracket is the relative spectrum line strength.As shown in the table; The STI571 beta crystal that the present invention prepares and the S0146 of Switzerland's Novartis criticize the STI571 beta crystal three's among STI571 sheet, the patent CN1134430C X diffraction data, thereby the crystal formation of the STI571 of checking the present invention preparation is a beta crystal.
The invention has the advantages that: preparation technology is simple, need not introduce beta-crystal as crystal seed, can prepare to have good mobility; Thermodynamically stable; Water absorbability is less relatively, and the STI571 of the beta crystal that is easier to store and process more is applicable to suitability for industrialized production.
Description of drawings
Fig. 1 for S0146 criticize the STI571 sheet (manufacturer: X-ray diffractogram Novartis Pharma Schweiz AG), judge that according to this figure the crystal formation of STI571 in tablet is the β type.
Fig. 2 is the X-ray diffractogram of the STI571 of the beta crystal of the present invention's preparation, judges that according to this figure the crystal formation of STI571 is the β type.
Fig. 3 randomly draws the DSC figure of a duplicate samples for the STI571 of the beta crystal of the present invention's preparation; DSC is a kind of dynamic differential calorimetry technology; Adopt this technology, until using ultra dependent sensor to detect thermal change, promptly neither endothermic nor exothermic reacts through heated sample; Can measure crystal and begin the fused temperature, show among the figure that it is 216.2 ℃ that STI571 begins the fused temperature.
Embodiment
Below in conjunction with embodiment the present invention is further specified.
Embodiment 1:
The 6.706g STI571 is joined in the 250ml single port bottle, add the 100ml acetonitrile and stir into suspension, under 80 ℃ of reflux states, add 28ml methyl alcohol, get yellow settled solution; Stop heating, be cooled to room temperature crystallization 23h under whipped state then naturally; Suction filtration, filter cake wash with 30ml second eyeball; 60 ℃ of forced air dryings get white solid 4.103g, and yield is 61.18%.
The STI571 fusing point of the beta crystal that makes: 216.1～216.8 ℃.
Embodiment 2:
The 5.582g STI571 to 250ml single port bottle, is added 150ml methyl alcohol and makes it dissolving; Remove most methyl alcohol under reduced pressure, get yellow oil; Add the 100ml acetonitrile, and under agitation, be incubated 2h down in 60 ℃; Naturally reduce to room temperature then; Suction filtration, filter cake washes with the 20ml acetonitrile; 60 ℃ of forced air dryings get white solid 4.728g, and yield is 84.70%.
The STI571 fusing point of the beta crystal that makes: 215.3～216.2 ℃.
Claims (8)
1. the preparation method of a STI571 beta crystal; It is characterized in that the STI571 of unformed STI571 or other crystal formation is dissolved in the mixed solvent of methyl alcohol and acetonitrile; Under-30～82 ℃ of conditions, be incubated crystallization; Crystallization time is 2～48h, obtains the STI571 beta crystal.
2. the preparation method of STI571 beta crystal according to claim 1; It is characterized in that standard, the STI571 of unformed STI571 or other crystal formation is dissolved in the mixed solvent of methyl alcohol and acetonitrile according to 5～30ml/g.
3. the preparation method of STI571 beta crystal according to claim 1 is characterized in that in the mixed solvent of methyl alcohol and acetonitrile, methyl alcohol accounts for 5～99% of mixed solvent TV.
4. the preparation method of STI571 beta crystal according to claim 3 is characterized in that methyl alcohol accounts for 10～40% of mixed solvent TV.
5. the preparation method of STI571 beta crystal according to claim 1 is characterized in that Tc is 20～60 ℃.
6. the preparation method of STI571 beta crystal according to claim 1 is characterized in that crystallization time is 2～6h.
7. the preparation method of STI571 beta crystal according to claim 1, the fusing point of the STI571 beta crystal that it is characterized in that preparing is lower than 217 ℃, and this fusing point is defined as beginning fused temperature in the differential scanning calorimetric analysis.
8. the preparation method of STI571 beta crystal according to claim 1, the STI571 beta crystal that it is characterized in that preparing is under following refraction angle 2 θ, and the relative spectrum line strength that the spectral line in its x-ray diffraction pattern has is 20 or higher: 9.5 °, 13.7 °; 17.2 °, 17.9 °, 19.8 °, 20.3 °; 20.8 °, 21.8 °, 22.5 °; 23.5 °, 29.5 °, 30.6 °.
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| CN2012100528225A CN102617549A (en) | 2012-03-02 | 2012-03-02 | Method for preparing imatinib mesylate beta crystalline form |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503825A (en) * | 2015-12-16 | 2016-04-20 | 齐鲁天和惠世制药有限公司 | Preparation method of imatinib mesylate beta-form crystal |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
| CN101573350A (en) * | 2006-04-27 | 2009-11-04 | 西科尔公司 | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha |
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2012
- 2012-03-02 CN CN2012100528225A patent/CN102617549A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
| CN101573350A (en) * | 2006-04-27 | 2009-11-04 | 西科尔公司 | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha |
Non-Patent Citations (1)
| Title |
|---|
| 李铭东等: "甲磺酸伊马替尼的合成", 《中国药学杂志》, vol. 43, no. 3, 29 February 2008 (2008-02-29) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503825A (en) * | 2015-12-16 | 2016-04-20 | 齐鲁天和惠世制药有限公司 | Preparation method of imatinib mesylate beta-form crystal |
| CN105503825B (en) * | 2015-12-16 | 2019-01-11 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of imatinib mesylate beta crystal |
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Application publication date: 20120801 |